Modeling Drkn Sh3 Domain Using Sequence Specific Wormlike Chain Model

Abstract

Though the wormlike chain (WLC) model has successfully described the statistical properties of fully denatured polypeptides, the lack of sequence details and attractive forces made it less successful in describing unfolded states in folding conditions. To cover the limitation while keeping the model's efficient feature, we have developed a sequence specific wormlike chain model. Computationally, secondary structure constraints from the secondary chemical shift measurements of drkN are integrated into the construction of each wormlike chain. Then the probability distribution is reweighted to bias compact conformations in which residues of similar hydrophobicity are located near each other. This model has been tested on two mutants (C2 and C60) of the Drosophila drk N-terminal (drkN) SH3 domain. drkN exists in approximately 1:1 equilibrium between folded and unfolded state in water, which gives us the opportunity to monitor the contact quenching of tryptophan 36 by either cysteine under all denaturing conditions. The experimental results exhibit a relatively slow kinetics, which implies slow intramolecular diffusion. The reweighted pairwise distance distributions are also compared to the Paramagnetic Relaxation Enhancement (PRE) data for drkN.